Fulvestrant, or 7-alpha-[9-(4,4,5,5,5-pentafluoropentyl-sulphonyl)nonyl]estra-1,3,5-(10)-triene-3,17-beta-diol taught by Patent GB 8327256 in 1983, is a white powder having a molecular weight of 606.77. Fulvestrant is the active principle of the commercial product Faslodex, AstraZeneca. Faslodex is commercialized as a composition to be preserved at refrigerator temperature in the form of an oily injectable solution containing 250 mg fulvestrant dissolved in 5 mL solvent. The solvent comprises 10% w/v ethyl alcohol, 10% w/v benzyl alcohol, 15% w/v benzyl benzoate and a sufficient amount of castor oil to complete 100% w/v (8).
Fulvestrant is indicated for the treatment of post-menopausal women with locally advanced or metastatic breast cancer and with positive estrogenic receptor, where the disease has relapsed during or after adjuvant treatment with antiestrogens or where the disease has progressed during antiestrogen treatment (8).
Faslodex is provided in prefilled sterile syringes for a single patient containing 50 mg/mL fulvestrant whether as a single 5 mL injection or as two concurrent 2.5 mL injections for administering a monthly dose. Faslodex is administered as an intramuscular injection of 250 mg once a month (8).
The present invention consists of a solid fulvestrant composition having enhanced solubility characteristics as compared to the solubility of the solid active principle, which is achieved by solubilization of fulvestrant in a lyophilization solvent and a drying process, preferably lyophilization. This new composition is capable of being commercialized as a dry powder, separately from a solubilizing composition to be mixed before the injection. This new formulation comprising said solid composition and said solubilizing composition provide greater stability, as the solid is less reactive than the solution. The preferred form of the present invention is an amorphous fulvestrant solid, more preferably lyophilized.
US 2007/0116729 describes, in claim 1, a method of lyophilization comprising two stages: first the material is dissolved in a solvent for said material to form a solution or to make a slurry of the material and pH is adjusted to dissolve the drug to form a solution; then a non-solvent is added for said material to said solution, wherein the non-solvent is miscible with said solvent to force said material at least partially out of said solution, and wherein said non-solvent is vaporizable under freeze-drying conditions. In claim 4 of said document it is established that if the material is hydrophobic and/or lipophylic said solvent is selected from the group consisting of 5 to 7-membered heteroring systems and claim 5 mentions that the solvent of claim 4 is selected from the group of tetrahydrofuran, tetrahydropyran, dioxane, and trioxane. In claim 44 of said document fulvestrant is mentioned. As indicated in this document, when the materials are lipophylic the solvent is selected from the group consisting of 5 to 7-membered heteroring systems. The present invention employs acetic acid, dimethylsulfoxide, or tert-butanol all of which have the following advantages: melting point from 15 to 25° C. which favors the lyophilization process, are considered as solvents of very low toxicity and minor risk for human health (class 3 solvents according to ICH (9)) and accordingly they are suitable for pharmaceutical use. By contrast, tetrahydrofuran has a melting point of −108 C, which hinders or prevents its solidification and hence its lyophilization; further, together with dioxane they are recommended as solvents of limited use in pharmaceutical products, both being solvents class 2 according to ICH. There is no information on tetrahydropyran and trioxane solvents in pharmaceutical products nor are they present in the list of residual solvents of ICH. Further, the non-solvent mentioned in this patent document is included in the group of mono-, di- or tri-hydro alcohols of 1 to 4 carbon atoms, and it should be noted that fulvestrant is highly soluble in ethanol (3) and in tert-butanol (7) so that on the contrary of what is established in this document they could not be used as non-solvents; in the present invention the non-solvent is water. Furthermore, US 2007/0116729 claims a solvent selected from the group of liquid polyethylene glycols and propylene glycol as a lyophilization solvent; it is noted that according to (7) fulvestrant solubility in propylene glycol is 4 mg/ml, and that its solubility in polyethylene glycol 400 is 22.5 mg/mL; considering that for therapeutic purposes 250 mg of fulvestrant should be administered in a volume of less than or equal to 5 mL which is the maximum volume recommended for intramuscular injection (3), when using these solvents at least 62.5 mL and 11 mL of propylene glycol and polyethylene glycol 400, respectively, would be required, which makes these solvents inadequate for use in a sustained-release pharmaceutical product comprising Fulvestrant to be administered intramuscularly or subcutaneously; in the latter route of administration only up to 3 milliliters may be administered (9). The solid pharmaceutical composition of fulvestrant of the present invention, at a concentration of at least 50 mg/mL, is dissolved in a solvent comprising castor oil and mixtures of alcohols, over a period of less than 2 minutes, which makes it suitable as a pharmaceutical product, further presenting the advantage of a greater chemical stability as a function of temperature over Faslodex, and since the manufacture process of the lyophilizate is carried out in an oxygen-free environment, where oxygen is responsible of oxidation of fulvestrant into a sulphone fulvestrant impurity, the formulation of the present invention may be stored without stability concerns at 25° C., whereas Faslodex must be stored at 2 to 8 C. Thus, the composition of the present invention does not need to be stored in a refrigerator in climatic zones I and II, as is the case of Faslodex.
U.S. Pat. No. 6,774,122 discloses a method for the treatment of breast or reproductive tract diseases comprising administering an injection containing fulvestrant in a carrier of ethanol, benzyl alcohol, benzyl benzoate, and castor oil. Said document teaches that although fulvestrant is significantly more soluble in castor oil than in any other tested oil, it may not be dissolved only in an oil-based solvent to achieve a sufficiently high concentration for administering a low-volume injection to a patient and obtain a therapeutically significant release rate. This problem is solved by the addition of organic solvents in which fulvestrant is very soluble and which are soluble in castor oil as an alcohol, and it was found by adding a non-aqueous ester-type solvent miscible with castor oil, together with these organic solvents, surprisingly a solubility of at least 50 mg/mL of fulvestrant was achieved. Also said document describes a flowchart of the manufacturing process characterized by the following steps: fulvestrant is mixed with alcohol and benzyl alcohol and stirred until it is completely dissolved. Benzyl benzoate is added, then castor oil up to the established final weight and the solution is stirred. This manufacturing sequence is required, as a rapid dissolution of fulvestrant in castor oil is not achieved, even if it contains an alcohol. By first adding solvents capable of solubilizing it and castor oil at the end, a high concentration of active is ensured. Fulvestrant solubility in these solvents is described in the same document, establishing that fulvestrant is a particularly lipophylic molecule, even when compared to other steroidal compounds.
U.S. Pat. No. 7,456,160, which is a continuation of U.S. Pat. No. 6,774,122, extends the percentage range of the constituents of the fulvestrant solution to a range from 10 to 30% w/v of ethyl alcohol and benzyl alcohol, a range from 10 to 25% w/v of benzyl benzoate and sufficient castor oil to complete 100% w/v.
U.S. Pat. No. 5,183,814, which mentions fulvestrant as a pure antiestrogen, describes a liquid formulation containing 50 mg of fulvestrant dissolved in 400 mg of benzyl alcohol and a sufficient amount of castor oil to complete 1 mL solution. The use of a solid composition is not suggested.
PCT/GB02/03092 describes certain liquid fulvestrant formulations, preferably at 100 mg/mL. The formulations contain at least 10% w/v or more of an alcohol, 5% w/v or more of a non-aqueous ester and 5% w/v or more of a ricinoleate excipient.
EP 1409021 describes in detail a liquid formulation containing fulvestrant, a ricinoleate excipient, a non-aqueous ester, an alcohol, and an antioxidant. In the same document it is affirmed that the invention is based on the discovery that addition of an antioxidant may improve the stability of fulvestrant formulations. Addition of an antioxidant is not required for the composition of the present invention, firstly because it is solid and furthermore because by the end of the lyophilization process, the lyophilizer is filled with nitrogen. Once the filling is completed and before opening the lyophilizer, the vials are capped and thus the vials containing fulvestrant remain filled with nitrogen, as is common in the process of sealing pharmaceutical products, thereby reducing the risk of oxidation.
EP 1272195 discloses the use of fulvestrant for preparing a medicament for the treatment of a patient with breast cancer who had been treated previously with an aromatase inhibitor and tamoxifene but failed. The formulations described in said document are liquid solutions containing fulvestrant.
WO 2007/033434 discloses a solution containing fulvestrant and at least one pharmaceutically acceptable alcohol, propylene glycol or a polyethylene glycol and castor oil.
US 2009/0227549 discloses a liquid formulation of fulvestrant in a pharmaceutically acceptable carrier, without castor oil or castor oil derivatives.
The present invention solves the problem by providing solid fulvestrant which is soluble in a solubilizing composition, to be mixed before being injected in a mammal for the oncological treatment. Prior art solids of fulvestrant do not ensure solubility in a solution comprising alcohols and castor oil. In particular, the prior art requires a first dissolution of the active matter in an alcohol before adding castor oil. The present invention allows for obtaining solid fulvestrant suitable to be stored as a medicament at room temperature with no risk of degradation. It is known that fulvestrant is sensitive to oxidation into its sulfoxide function to produce the sulphone derivative, one of the major degradation products, and thus it is important to remove oxygen from the pharmaceutical formulations in order to improve preservation conditions and shelf life of the medicament. Full removal of oxygen in liquid formulations is a complicated process as it includes removing the oxygen from the air chamber of the packages, as well as the oxygen dissolved in the employed solvents. The present invention substantially simplifies the process of oxygen removal because at the end of the lyophilization process the product is in a chamber under very high vacuum which is disrupted with a gas from which oxygen has been almost entirely removed, for example highly pure nitrogen. The process ends with the tight sealing of vials inside the lyophilization chamber and thereby the solid product will remain in an oxygen-free atmosphere throughout its shelf life.
The present invention further consists of Fulvestrant in a new solid physical state and a process for manufacturing the same, which may be adapted for large-scale commercial production, thus allowing for obtaining a pharmaceutical-grade product. This new solid state is characterized by an X-ray diffraction pattern with no defined peaks and by not having a melting point.
The present invention also provides a formulation comprising said pharmaceutical solid fulvestrant composition in combination with a solubilizing composition, said composition comprising castor oil with alcohol, in the absence of other components such as benzyl benzoate, indicated in the state-of-the-art as essential for achieving solubility of the active ingredient fulvestrant. The prior art does not describe or suggest a formulation as that of the present invention nor anticipates that fulvestrant may be soluble in a castor oil and alcohol solution in less than 2 minutes, at concentrations suitable for pharmaceutical use. This is achieved with the formulation of the present invention.